Synaptic mitochondria associated with memory retrieval in wild-type and amyloid precursor protein transgenic mice

Rhodes, Adam James (2019) Synaptic mitochondria associated with memory retrieval in wild-type and amyloid precursor protein transgenic mice. Masters thesis, University of Central Lancashire.

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Research in memory and Alzheimer’s Disease (AD) stands to benefit from a deeper understanding of the molecular processes behind long-term in-vivo memory retrieval, which is a central aim of this thesis. Purified synaptosomes were prepared from wild-type (WT) and amyloid-precursor protein transgenic (APPtg) mice undergoing spatial memory retrieval in the water- maze. These synaptosomes underwent an unbiased proteomic analysis to identify pathways for Western blotting. A combination of statistical tools including gene-set enrichment analysis (GSEA), gene-ontology (GO), and protein-protein interaction (PPI) networks, indicated that the largest and most significant group of proteins upregulated are involved in oxidative phosphorylation. However, these broad statistical tools were not sensitive enough to reveal the source of the memory retrieval dysfunction in the APPtg mice, thus, ranked proteins were tested to reveal genotype- memory interaction effects. The largest group of interacting proteins identified are connected to mitochondrial dynamics, such as the fusion protein Optic Atrophy 1 (OPA1), the mitochondrial calcium uniporter (MCU) involved in Ca2+ overload and Myosin-VI involved in mitophagic trafficking. The proteomics identified the Ubiquitin-conjugating enzyme E2N (UBE2N), which is the main enzyme for promoting the formation of the lysine-63 (K63) linked ubiquitin modifications, associated with both synaptic strengthening and autophagy. To overcome the problem of in-vivo stimulation producing both synaptic
strengthening and weakening, along with insoluble SDS-resistant proteins hindering Western blot analysis, markers of mitochondrial dynamics such as Fis1 and OPA1 were anchored to changes in K63-ubiquitin. This showed a potential positive association between long- term memory increases in K63-ubiquitin in concordance with dynamic changes in OPA1 and Fis1. The interpretation is that bidirectional transport at the synapse in the context of long-term memory has increased the quality, but not the quantity, of the mitochondrial organelle. An evidence driven, abductive theoretical framework for understanding the role of mitochondrial dynamics in memory processing at synapses was proposed called memory-enhancing- mitochondrial-evolution-at-synapses (MEMES), suggesting that synaptic mitohormesis is the causal driver of cognitive reserve through evolutionary processes that fundamentally control memory encoding and retrieval. This research may have important implications for a new era of memory research, preclinical diagnosis and mitochondrial medicine.

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